Quaternary basic amides, method of preparing them and pharmaceutical compositions in which they are present

ABSTRACT

The invention relates to quaternary basic amides of the formula ##STR1## in which Ar is an optionally substituted mono-, di- or tri-cyclic aromatic or heteroaromatic group; 
     T is a direct bond, a hydroxymethylene group, an alkoxymethylene group in which the alkoxy group is C 1  -C 4 , or a C 1  -C 5  -alkylene group; 
     Ar&#39; is an unsubstituted or mono- or poly-substituted phenyl, a thienyl, a benzothienyl, a naphthyl or an indolyl; 
     R is hydrogen or a C 1  -C 4  -alkyl, or a C 1  -C 4  -ω-alkoxy(C 2  -C 4 )alkyl, or a C 2  -C 4  -ω-alkanoyloxy (C 1  -C 4 )alkyl; 
     Q is hydrogen; 
     or else Q and R together form a 1,2-ethylene, 1,3-propylene or 1,4-butylene group; 
     Am.sup.⊕ is the radical ##STR2## in which X 1 , X 2  and X 3 , together with the nitrogen atom to which they are bonded, form a 1-azoniabicyclo 2.2.2!octane optionally substituted by a phenyl or benzyl group; and 
     A.sup.⊖ is a pharmaceutically acceptable anion. 
     These compounds are useful for the preparation of drugs intended for the treatment of pathological conditions involving the tachykinin system.

The present application is a continuation-in-part of U.S. applicationSer. No. 08/239,417, filed May 6, 1994, now U.S. Pat. No. 5,583,134,which is a continuation-in-part of U.S. application Ser. No. 08/129,311,filed Sep. 30, 1993, now abandoned.

The present invention relates to novel quaternary basic amides, to amethod of preparing them and to the pharmaceutical compositions in whichthey are present as active principles.

More particularly, the present invention relates to a novel class ofquaternary basic amides for therapeutic use in pathological phenomenainvolving the tachykinin system, such as: pain (D. Regoli et al., LifeSciences, 1987, 40, 109-117), allergy and inflammation (J. E. Morlay etal., Life Sciences, 1987, 41, 527-544), circulatory insufficiency (J.Losay et al., 1977, Substance P, Von Euler, U.S. and Pernow ed.,287-293, Raven Press, New York), gastrointestinal disorders (D. Regoliet al., Trends Pharmacol. Sci., 1985, 6, 481-484) and respiratorydisorders (J. Mizrahi et al., Pharmacology, 1982, 25, 39-50), theseexamples being neither limiting nor exclusive.

Ligands endogenous to the tachykinin receptors have been described, suchas substance P (SP), neurokinin A (NK_(A)) (S. J. Bailey et al., 1983,Substance P, P. Skrabanck ed., 16-17 Boole Press, Dublin) and neurokininB (NK_(B)) (S. P. Watson, Life Sciences, 1983, 25, 797-808).

Thus, according to one of its features, the present invention relates toquaternary basic amides of the formula ##STR3## in which Ar is anoptionally substituted mono-, di- or tri-cyclic aromatic orheteroaromatic group;

T is a direct bond, a hydroxymethylene group, an alkoxymethylene groupin which the alkoxy group is C₁ -C₄, or a C₁ -C₅ -alkylene group;

Ar' is a phenyl which is unsubstituted or mono- or poly-substituted by asubstituent selected from: a halogen atom, preferably a chlorine orfluorine atom, a trifluoromethyl, a C₁ -C₄ -alkoxy or a C₁ -C₄ -alkyl,said substituents being identical or different, a thienyl, abenzothienyl, a naphthyl or an indolyl;

R is hydrogen or a C₁ -C₄ -alkyl, or a ω-(C₁ -C₄) alkoxy(C₂ -C₄)alkyl,or a ω-(C₂ -C₄)alkanoyloxy (C₁ -C₄) alkyl;

Q is hydrogen;

or else Q and R together form a 1,2-ethylene, 1,3-propylene or1,4-butylene group;

Am.sup.⊕ is the radical ##STR4## in which X₁ , X2 and X3 , together withthe nitrogen atom to which they are bonded, form an azabicyclic orazatricyclic system optionally substituted by a phenyl or benzyl group;and

A' is a pharmaceutically acceptable anion.

The pharmaceutically acceptable anions are those normally used to salifythe quaternary ammonium ions of products for pharmaceutical use,preferably chloride, bromide, iodide, hydrogensulfate, methanesulfonate,paratoluenesulfonate, acetate and benzenesulfonate ions.

In particular, in formula (I), Ar is a mono-, di- or tri-cyclic aromaticor heteroaromatic group which can carry one or more substituents and inwhich a carbon atom of the aromatic carbocycle or aromatic heterocycleis directly bonded to T.

More particularly, the radical Ar can be a phenyl group which may beunsubstituted or may optionally contain one or more substituents.

If Ar is a phenyl group, this can preferably be mono- or di-substituted,especially in the 2,4-position but also for example in the 2,3-, 4,5-,3,4- or 3,5-position; it can also be trisubstituted, especially in the2,4,6-position but also for example in the 2,3,4-, 2,3,5-, 2,4,5- or3,4,5-position, tetrasubstituted, for example in the 2,3,4,5-position,or pentasubstituted. The substituents of the phenyl group can be: F; Cl;Br; I; CN; OH; NH₂ ; NH--CONH₂ ; NO₂ ; CONH₂ ; CF₃ ; C₁ -C₁₀ -alkyl,preferably C₁ -C₄ -alkyl, methyl or ethyl being preferred, as well as,for example, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, pentyl or n-pentyl, hexyl or n-hexyl, octyl or n-octyl,nonyl or n-nonyl or decyl or n-decyl; alkenyl containing 2 to 10 carbonatoms, preferably 2-4 carbon atoms, for example vinyl, allyl,prop-1-enyl, isopropenyl, butenyl or but-1-en-1-, -2-, -3- or -4-yl,but-2-en-1-yl, but-2-en-2-yl, pentenyl, hexenyl or decenyl; alkynylcontaining 2 to 10 carbon atoms, preferably 2-4 carbon atoms, forexample ethynyl, prop-1-yn-1-yl, propargyl, butynyl or but-2-yn-1-yl,pentynyl or decynyl; cycloalkyl containing 3 to 8 carbon atoms,preferably 5 or 6 carbon atoms, cyclopentyl or cyclohexyl beingpreferred, as well as, for example, cyclopropyl, cyclobutyl, 1-, 2- or3-methylcyclopentyl, 1-, 2-, 3- or 4-methylcyclohexyl, cycloheptyl orcyclooctyl; bicycloalkyl containing 4 to 11 carbon atoms, preferably 7carbon atoms, exo- or endo-2-norbornyl being preferred, as well as, forexample, 2-isobornyl or 5-camphyl; hydroxyalkyl containing 1 to 5 carbonatoms, preferably 1-2 carbon atoms, hydroxymethyl and 1- or2-hydroxyethyl being preferred, as well as, for example,1-hydroxyprop-1-yl, 2-hydroxyprop-1-yl, 3-hydroxyprop-1-yl,1-hydroxyprop-2-yl, 1-hydroxybut-1-yl or 1-hydroxypent-1-yl; alkoxycontaining 1 to 10 carbon atoms, preferably 1-4 carbon atoms, isopropoxyor ethoxy being preferred, as well as, for example, n-propoxy, methoxy,n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, hexyloxy,heptyloxy, octyloxy, nonyloxy or decyloxy; alkoxyalkyl containing 2 to10 carbon atoms, preferably from 2 to 6 carbon atoms, for examplealkoxymethyl or alkoxyethyl, such as methoxymethyl or 1- or2-methoxyethyl, 1- or 2-n-butoxyethyl or 1- or 2-n-octyloxyethyl;alkoxyalkoxyalkyl containing up to 10 carbon atoms, preferably from 4 to7 carbon atoms, for example alkoxyalkoxymethyl such as2-methoxyethoxymethyl, 2-ethoxyethoxymethyl or 2-isopropoxyethoxymethyl,or alkoxyalkoxyethyl such as 2-(2-methoxyethoxy)ethyl or2-(2-ethoxyethoxy)ethyl; alkoxyalkoxy containing from 2 to 10 carbonatoms, preferably from 3 to 6 carbon atoms, for example 2-methoxyethoxy,2-ethoxyethoxy or 2-n-butoxyethoxy; alkenyloxy containing 2 to 10 carbonatoms, preferably 2 to 4 carbon atoms, allyloxy being preferred, as wellas, for example, vinyloxy, propenyloxy, isopropenyloxy, butenyloxy suchas but-1-en-1-, -2-, -3- or -4-yloxy, but-2-en-1-yloxy orbut-2-en-2-yloxy, pentenyloxy, hexenyloxy or decenyloxy; alkenyloxyalkylhaving up to 10 carbon atoms, preferably 3-6 carbon atoms, for exampleallyloxymethyl; alkynyloxy containing from 2 to 10 carbon atoms,preferably 2 to 4 carbon atoms, propargyloxy being preferred, as wellas, for example, ethynyloxy, prop-1-yn-1-yloxy, butynyloxy orbut-2-yn-1-yloxy, pentynyloxy or decynyloxy; alkynyloxyalkyl containingfrom 3 to 10 carbon atoms, preferably 3 to 6 carbon atoms, for exampleethynyloxymethyl, propargyloxymethyl or 2-(but-2-yn-1-yloxy)ethyl;cycloalkoxy containing 3 to 8 carbon atoms, preferably 5 or 6 carbonatoms, cyclopentoxy or cyclohexyloxy being preferred, as well as, forexample, cyclopropoxy, cyclobutoxy, 1-, 2- or 3-methylcyclopentoxy, 1-,2-, 3- or 4-methylcyclohexyloxy, cycloheptyloxy or cyclooctyloxy;alkylthio containing from 1 to 10 carbon atoms, preferably 1 to 4 carbonatoms, methylthio or ethylthio being preferred, as well as, for example,n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio,tert-butylthio, pentylthio, hexylthio, octylthio, nonylthio ordecylthio; alkylthioalkyl containing from 2 to 10 carbon atoms,preferably 2 to 6 carbon atoms, for example methylthiomethyl,2-methylthioethyl or 2-n-butylthioethyl; acylamino, namely alkanoylaminocontaining from 1 to 7 carbon atoms, preferably 1 to 4 carbon atoms,formylamino and acetylamino being preferred, as well as propionylamino,butyrylamino, isobutyrylamino, valerylamino, caproylamino orheptanoylamino, or aroylamino or benzylamino; acylaminoalkyl, preferablyalkanoylaminoalkyl containing from 2 to 8 carbon atoms, preferably 3 to6 carbon atoms, such as formylaminoethyl, acetylaminoethyl,propionylaminoethyl, n-butyrylaminoethyl, formylaminopropyl,acetylaminopropyl, propionylaminopropyl, formylaminobutyl oracetylaminobutyl, as well as propionylaminobutyl or butyrylaminobutyl;acyloxy containing from 1 to 6 carbon atoms, preferably 2 to 4 carbonatoms, acetoxy, propionyloxy or butyryloxy being preferred, as well as,for example, formyloxy, valeryloxy or caproyloxy; alkoxycarbonylcontaining from 2 to 5 carbon atoms, preferably 2 or 3 carbon atoms,methoxycarbonyl and ethoxycarbonyl being preferred, as well as, forexample, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl,isobutoxycarbonyl, sec-butoxycarbonyl or tert-butoxycarbonyl;cycloalkoxycarbonyl containing from 4 to 8 carbon atoms, preferably 6 or7 carbon atoms, cyclopentoxycarbonyl and cyclohexyloxycarbonyl beingpreferred, as well as cyclopropoxycarbonyl, cyclobutoxycarbonyl orcycloheptyloxycarbonyl; alkylaminocarbonylamino containing from 2 to 4carbon atoms, such as methylaminocarbonylamino, ethylaminocarbonylaminoor propylaminocarbonylamino; dialkylaminocarbonylamino containing from 3to 7 carbon atoms, preferably 3 to 5 carbon atoms,dimethylaminocarbonylamino being preferred, as well asdi-n-propylaminocarbonylamino or diisopropylaminocarbonylamino;(pyrrolidin-1-yl)carbonylamino; cycloalkylaminocarbonylamino containingfrom 4 to 8 carbon atoms, preferably 6 or 7 carbon atoms,cyclopentylaminocarbonylamino and cyclohexylaminocarbonylamino beingpreferred, as well as cyclopropylaminocarbonylamino,cyclobutylaminocarbonylamino or cycloheptylaminocarbonylamino;alkylaminocarbonylaminoalkyl containing from 3 to 9 carbon atoms,preferably 4 to 7 carbon atoms, methylaminocarbonylaminoethyl,ethylaminocarbonylaminoethyl, ethylaminocarbonylaminopropyl andethylaminocarbonylaminobutyl being preferred, as well as, for example,methylaminocarbonylaminomethyl, n-propylaminocarbonylaminobutyl andn-butylaminocarbonylaminobutyl; dialkylaminocarbonylaminoalkylcontaining from 4 to 11 carbon atoms, for exampledimethylaminocarbonylaminomethyl, diethylaminocarbonylaminoethyl,diethylaminocarbonylaminopropyl and diethylaminocarbonylaminobutyl;(pyrrolidin-1-yl)carbonylaminoethyl; (piperidin-1-yl)carbonylaminoethyl;cycloalkylaminocarbonylaminoalkyl containing from 5 to 12 carbon atoms,preferably 8 to 11 carbon atoms, cyclopentylaminocarbonylaminoethyl,cyclopentylaminocarbonylaminopropyl, cyclopentylaminocarbonylaminobutyl,cyclohexylaminocarbonylaminoethyl, cyclohexylaminocarbonylaminopropyland cyclohexylaminocarbonylaminobutyl being preferred, as well as, forexample, cyclopropylaminocarbonylaminoethyl orcycloheptylaminocarbonylaminoethyl; alkoxycarbonylaminoalkyl containingfrom 3 to 12 carbon atoms, preferably 4 to 9 carbon atoms,methoxycarbonylaminoethyl, ethoxycarbonylaminoethyl,n-propoxycarbonylaminoethyl, isopropoxycarbonylaminoethyl,n-butoxycarbonylaminoethyl, isobutoxycarbonylaminoethyl,sec-butoxycarbonylaminoethyl, tert-butoxycarbonylaminoethyl,ethoxycarbonylaminopropyl, n-butoxycarbonylaminopropyl,ethoxycarbonylaminobutyl and n-butoxycarbonylaminobutyl being preferred,as well as, for example, n-propoxycarbonylaminopropyl,n-propoxycarbonylaminobutyl or isopropoxycarbonylaminobutyl;cycloalkoxycarbonylaminoalkyl containing from 5 to 12 carbon atoms,preferably 8 to 11 carbon atoms, cyclopentoxycarbonylaminoethyl,cyclopentoxycarbonylaminopropyl, cyclopentoxycarbonylaminobutyl,cyclohexyloxycarbonylaminoethyl, cyclohexyloxycarbonylaminopropyl andcyclohexyloxycarbonylaminobutyl being preferred, as well as, forexample, cyclopropoxycarbonylaminomethyl orcycloheptyloxycarbonylaminoethyl; carbamoylalkyl containing from 2 to 5carbon atoms, preferably 2 carbon atoms, carbamoylmethyl beingpreferred, as well as carbamoylethyl, carbamoylpropyl or carbamoylbutyl;alkylaminocarbenylalkyl containing from 3 to 9 carbon atoms, preferably3 to 6 carbon atoms, methylaminocarbonylethyl, ethylaminocarbonylmethyl,n-propylaminocarbonylmethyl, isopropylaminocarbonylmethyl,n-butylaminocarbonylmethyl, isobutylaminocarbonylmethyl,sec-butylaminocarbonylmethyl and tert-butylaminocarbonylmethyl beingpreferred, as well as, for example, ethylaminocarbonylethyl,ethylaminocarbonylpropyl, ethylaminocarbonylbutyl,propylaminocarbonylbutyl or n-butylaminocarbonylbutyl;dialkylaminocarbonylalkyl containing from 4 to 11 carbon atoms,preferably 4 to 8 carbon atoms, dimethylaminocarbonylmethyl,diethylaminocarbonylmethyl and di-n-propylaminocarbonylmethyl beingpreferred, as well as, for example, diethylaminocarbonylethyl,diethylaminocarbonylpropyl or diethylaminocarbonylbutyl;(pyrrolidin-1-yl)carbonylmethyl; (piperidin-1-yl)carbonylmethyl;(piperidin-1-yl)carbonylethyl; cycloalkylaminocarbonylalkyl containingfrom 5 to 12 carbon atoms, preferably 7 or 8 carbon atoms,cyclopentylaminocarbonylmethyl and cyclohexylaminocarbonylmethyl beingpreferred, as well as, for example, cyclopropylaminocarbonylmethyl,cyclobutylaminocarbonylmethyl, cycloheptylaminomethyl,cyclohexylaminocarbonylethyl, cyclohexylaminocarbonylpropyl orcyclohexylaminocarbonylbutyl; alkylaminocarbonylalkoxy containing from 3to 10 carbon atoms, preferably 3 to 5 carbon atoms,methylaminocarbonylmethoxy being preferred, as well as, for example,methylaminocarbonylethoxy or methylaminocarbonylpropoxy;dialkylaminocarbonylalkoxy containing from 4 to 10 carbon atoms,preferably 4 to 7 carbon atoms, such as dimethylaminocarbonylmethoxy ordiethylaminocarbonylethoxy; (piperidin-1-yl)carbonylmethoxy; andcycloalkylaminocarbonylalkoxy containing from 5 to 11 carbon atoms,preferably 7 or 8 carbon atoms, such as cyclopentylaminocarbonylmethoxyor cyclohexylaminocarbonylmethoxy.

The radical Ar can also be a bicyclic aromatic group such as 1- or2-naphthyl or 1-, 2-, 3-, 4-, 5-, 6- or 7-indenyl, in which one or morebonds can be hydrogenated, it being possible for said groups to beunsubstituted or optionally to contain one or more substituents such as:a halogen, more particularly a fluorine atom, and alkyl, phenyl, cyano,hydroxyalkyl, hydroxy, C₁ -C₄ -alkoxy, oxo, alkylcarbonylamino,alkoxycarbonyl and thioalkyl groups in which the alkyls are C₁ -C₄.

The radical Ar can also be a pyridyl, thiadiazolyl, indolyl, indazolyl,imidazolyl, benzimidazolyl, quinolyl, benzotriazolyl, benzofuranyl,benzothienyl, benzothiazolyl, benzisothiazolyl, isoquinolyl,benzoxazolyl, benzoxazinyl, benzodioxinyl, isoxazolyl, benzopyranyl,thiazolyl, thienyl, furyl, pyranyl, chromenyl, isobenzofuranyl,pyrrolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl,phthalazinyl, quinazolinyl, acridinyl, isothiazolyl, isochromanyl orchromanyl group in which one or more double bonds can be hydrogenated,it being possible for said groups to be unsubstituted or optionally tocontain one or more substituents such as: alkyl, phenyl, cyano,hydroxyalkyl, hydroxy, alkylcarbonylamino, alkoxycarbonyl and thioalkylgroups in which the alkyls are C₁ -C₄.

Advantageously, the radical Ar is a phenyl which is unsubstituted ormono- or poly-substituted by a halogen atom, more particularly achlorine or fluorine atom, a trifluoromethyl, a C₁ -C₄ -alkyl, a hydroxyor a C₁ -C₄ -alkoxy, a naphthyl which is unsubstituted or mono- orpoly-substituted by a halogen, a trifluoromethyl, a C₁ -C₄ -alkyl, ahydroxy or a C₁ -C₄ -alkoxy, a pyridyl, a thienyl, an indolyl, aquinolyl, a benzothienyl or an imidazolyl.

The particularly preferred compounds are those of formula (I) in whichAr is a phenyl group substituted by an isopropoxy group, advantageouslyin the 3-position.

In formula (I), T is preferably a methylene group.

The substituents R and Q are preferably respectively, methyl andhydrogen; 2-methoxyethyl and hydrogen; 2-acetoxyethyl and hydrogen; or Rand Q form together a 1,3-propylene group.

The substituent Ar' is preferably a phenyl group advantageouslysubstituted by two chlorine atoms, more particularly in the 3- and4-positions.

The radical represented by Am.sup.⊕ preferably contains from 5 to 9carbon atoms in the azabicyclic or azatricyclic system.

The radical ##STR5## represented by the substituent Am.sup.⊕ in formula(I) is preferably the residue of an azabicyclic or azatricyclic systemselected from:

(a) 1-azoniabicyclo 2.2.0!hexane

(b) 1-azoniabicyclo 3.1.0!hexane

(c) 1-azoniabicyclo 2.2.1!heptane

(d) 1-azoniabicyclo 2.2.2!octane

(e) 1-azoniabicyclo 3.2.1!octane

(f) 1-azoniabicyclo 3.2.2!nonane

(g) 1-azoniabicyclo 3.3.1!nonane

(h) hexahydro-1H-pyrrolizinium-4

(i) octahydroindolizinium-4

(j) octahydro-2H-quinolizinium-5

(k) 1-azoniatricyclo 3.3.1.1³,7 !decane

(l) 4-phenyl-1-azoniabicyclo 2.2.2!octane,

the groups (d) and (l) being particularly preferred.

Particularly preferred quaternary basic amides according to the presentinvention are those of formula (I) in which simultaneously:

Ar is a 3-isopropoxyphenyl group;

T is a methylene group;

R and Q are respectively methyl and hydrogen; 2-acetoxyethyl andhydrogen; or R and Q form together a 1,3-propylene group;

Ar' is 3,4-dichlorophenyl;

Am.sup.⊕ is a radical (d) or (l) as defined above; and

A⁻ is a pharmaceutically acceptable anion, preferably chloride,methanesulfonate or benzenesulfonate. These products, of the formula##STR6## in which iPr is isopropyl, R' and Q' are respectively methyland hydrogen; 2-acetoxyethyl and hydrogen; or R' and Q' form together a1,3-propylene group, R" is hydrogen or a phenyl group and A⁻ is asdefined above, especially the methanesulfonate or chloride ion, arepotent substance P antagonists.

The compounds of formula (I') in which R' and Q' together form a1,3-propylene group are extremely potent and show a greater affinity forthe neurokinin-1 receptor than does substance P itself. They thereforeconstitute the preferred feature of the present invention.

Among these compounds, those of formula (I"): ##STR7## in which A.sup.⊖is a pharmaceutically acceptable anion, especially methanesulfonate,chloride and benzenesulfonate, are the most valuable.

According to another feature, the present invention relates to a methodof preparing the compounds of formula (I) above, which comprisestreating a derivative of the formula ##STR8## in which Y is anyremovable group, preferably a methanesulfonyl or benzenesulfonyl groupwith a cyclic tertiary amine of the formula ##STR9## in which X₁, X₂ andX₃, together with the nitrogen atom to which they are bonded, form anazabicyclic or azatricyclic system optionally substituted by a phenyl orbenzyl group, in an organic solvent, at a temperature between roomtemperature and 120° C., and isolating the resulting product, or else,if appropriate, exchanging the methanesulfonate anion of the resultingquaternary salt with another pharmaceutically acceptable anion.

The organic solvent used is preferably a polar aprotic solvent, forexample acetonitrile, N,N-dimethylformamide orN,N-dimethylphenylacetamide, but it is also possible to use an ether,for example tetrahydrofuran, dioxane or methyl t-butyl ether, or aketone, for example methyl ethyl ketone, acetonitrile being particularlypreferred.

In the temperature range indicated above, the preferred temperature is70°-90° C. If acetonitrile is used as the solvent, the reaction isadvantageously carried out at the reflux point of the reaction mixture.

The product obtained in this way is isolated by the usual techniques,for example by concentration of the solvents, then washing of theresidue with water and then purification by the conventional techniques,for example by chromatography or recrystallization.

The methanesulfonate anion resulting from the reaction between thetertiary amine of formula (III) and the methanesulfonyloxy derivative offormula (II) can be exchanged, in situ or after isolation of thecompound (I) in which A.sup.⊖ is the methanesulfonate ion, with anotheranion A.sup.⊖ by the conventional methods, for example by exchange in asolution such as a solution of hydrochloric acid in the case whereA.sup.⊖ is a chloride anion, or by exchange of the anion with anotheranion by elution of the compound (I) on an ion exchange resin, forexample Amberlite IRA68® or Duolite A375®.

The derivatives of formula (II) used as starting compounds for themethod of the present invention can be prepared according to Scheme 1below, where, in the formulae indicated: ##STR10##

In Scheme 1, the reactions in the various steps are shown in arepresentative way so as to indicate the type of said reactions withoutgiving the means employed, which are known.

Thus, for example, in Route A, step 2, and in Route B, step 6, "H₂ "means that the starting nitrile is subjected to reduction, for exampleto catalytic hydrogenation (Raney Ni in ethanol, in the presence ofammonia, to give the primary amine IV).

In the same step 2 of Route A, the term "alkylation" means that, afterreduction, the primary amine is subjected to an alkylation reactionwhich is either direct with an alkyl halide or sulfate, or indirect bymeans of acylation and reduction of the carbonyl group. Thus, forexample, reaction of the primary amine (IV) with ethyl chloroformate andreduction of the ethoxycarbonyl group gives the product of formula (IV)in which R is methyl, as described in EP-0 428 434 and EP-0 474 561. Thecompound of formula (IV) in which R is C₂ -C₄ -alkyl is prepared byreplacing the ethyl chloroformate with the chloride (or other functionalderivative) of a C₂ -C₄ -alkanoic acid and by reducing the carbonylgroup of the resulting N-acylated derivative. Replacing ethylchloroformate with ethyl ethyloxalyle, ethyl hemimalonate or ethylhemisuccinate, for example, gives the corresponding N-acyl derivatives.The carbonyl groups are then reduced according to the conventionalmethods to obtain the ω-hydroxy(C₂ -C₄)alkyl derivatives which areO-acylated or O-alkylated in order to obtain the ω-alkanoyloxyalkylderivatives or the ω-alkoxyalkyl derivatives of formula IV in which R isω-(C₂ -C₄)alkanoyloxy(C₂ -C₄)alkyl or ω-(C₁ -C₄)alkoxy(C₂ -C₄)alkyl.Likewise, replacing alkyl chloroformates with the chloride of an ω-(C₁-C₄) alkoxy(C₂ -C₄)alkanoic acid, followed by reduction as describedabove, directly gives the ω-alkoxyalkyl derivatives of formula IV inwhich R is ω-(C₁ -C₄)alkoxy(C₂ -C₄)alkyl.

Also, for example, in step 4 of Route A, "H⁺ " means that thetetrahydropyranyloxy group is subjected to acid hydrolysis under theconditions well known in the literature. ##STR11##

The meaning of the substituent Ar depends on the choice of acidHO--CO--T--Ar used in steps 3 and 8 in the form of one of its functionalderivatives. All these acids are well known in the literature, readilyprepared according to the literature or commercially available.

The meaning of the substituent Ar' depends on the choice of nitrileAr'--CH₂ --CN, which, on reaction with2-tetrahydropyranyloxy-1-bromoethane, hydrogenation of the resultingproduct and N-alkylation if appropriate (step 2), gives the amine.

Route A of Scheme 1 in which R═H, alkyl and Q═H is described in theliterature and in patent applications EP-A-0 428 434 and EP-A-0 474 561.

Route B of Scheme 1 involves a series of reactions well known to thoseskilled in the art, such as the alkylation of a nitrile with abrominated derivative in the presence of lithium diisopropylamide (LDA)(step 5), followed by reduction of the nitrile in the presence of acatalyst to give the corresponding amine after reduction of theintermediate amide (step 7) obtained during the cyclization (step 6),for example according to A. V. El'tsov et al., Biol. Soedin., Akad. NaukSSSR, 1965, 109-12 (CA, 1965, 63, 16299).

In both the routes of Scheme 1, the reaction conditions of certain stepsare the same. Thus the reduction of step 2 (Route A) and step 6 (RouteB) is carried out under the same conditions. Likewise, step 7 (Route B)and the reduction of the N-acylated derivative or the ethoxycarbonyl inthe indirect alkylation reaction of step 2 (Route B) take place underthe same conditions. Finally, the acylation in step 3 (Route A) and step8 (Route B) is carried out under the same conditions.

The method of preparing the compounds (I) according to the inventionconsists in reacting the derivative (II), prepared by reacting thealcohol (IV) with a YCl derivative, for example mesyl chloride orbenzenesulfonyl chloride (step 9), with a tertiary amine of formula(III) in accordance with Scheme 2 below. ##STR12##

Resolution of the racemic mixtures (I) makes it possible to isolate theenantiomers (I*), which also form part of the invention.

It is preferable, however, to resolve the racemates at the stage of theintermediate amino alcohols, which are capable of giving salts withoptically active acids. The amino alcohols correspond to the compounds(IV) and (V) obtained according to step 2 (Route A) and according tostep 7 (Route B) of Scheme 1 after deprotection of the compounds byhydrolysis in an acid medium: ##STR13## in which Ar' and R are asdefined for (I) and m is 1, 2 or 3.

The enantiomers are then separated by conventional methods such ascrystallization or chiral preparative high pressure chromatography.

The preparation of the optically pure compounds is illustrated in Scheme3 below, where "*" means that the carbon atom identified by this symbolhas the defined configuration (+) or (-).

In Scheme 3, the last step is indicated as being performed with the freeacid, but it can be carried out with a functional derivative thereof,which could attack the molecule on both the hydroxy group and the aminogroup. In this case, it is desirable to protect the hydroxy group again,for example with dihydropyran to form the tetrahydropyranyl ether.

The preparation of the compounds (VI*) according to Scheme 3 in which Ris hydrogen or a C₁ -C₄ -alkyl group and Q is hydrogen is described inEP-A-0 428 434 and EP-A-0 474 561. ##STR14##

The optically pure compounds of formula (VI*) in which Q and R arebonded together to form 1,2-ethylene, 1,3-propylene or 1,4-butylene areprepared in the same manner.

In particular, the compound (VII*) obtained after separation of theenantiomers of (VII) is coupled with an acid of the formula Ar--T--COOH,in the presence of a coupling agent, by the usual methods. As indicatedabove, it is possible to use a functional derivative of this acid, suchas the acid itself appropriately activated by cyclohexylcarbodiimide orby benzotriazolyl-N-oxytrisdimethylaminophosphonium hexafluorophosphate(BOP), for example, or else one of the functional derivatives whichreact with amines, for example an anhydride, a mixed anhydride, the acidchloride or an activated ester such as the paranitrophenyl ester.

The resulting compound of the formula ##STR15## is then reacted with aYCl derivative according to step 9 of Scheme 1 to give the opticallypure derivative (II).

The products of formula (I) in which T is a hydroxymethylene, C₁ -C₄-alkoxymethylene or C₂ -C₅ -alkylidene group possess two centers ofasymmetry. In this case, the diastereoisomers and the pure isomers canbe prepared by reacting the optically pure amino alcohol and either theoptically pure or the racemic acid HO--CO--T--Ar; in the latter case,the diastereoisomers can be separated for example by chromatography.

The reaction with the tertiary amine (III) makes it possible to preparethe product (I) according to the invention in optically pure form.

The amines of formula (III) are those described in the literature.

Among these amines, those which are preferred contain from 5 to 9 carbonatoms in the ring system and a nitrogen atom, examples being citedbelow:

(a') 1-azabicyclo 2.2.0!hexane prepared according to C. A. Grob et al.,Helv. Chim. Acta, 1964, (47), 8, 2145-55. ##STR16## (b') 1-azabicyclo3.1.0!hexane prepared according to A. L. Logothetis, J. Am. Chem. Soc. ,1965, (87), 4, 749-754. ##STR17## (c') 1-azabicyclo 2.2.1!heptaneprepared according to Gassman et al., J. Am. Chem. Soc., 1968, (90), 5,1355-6. ##STR18## (d') 1-azabicyclo 2.2.2!octane or quinuclidine.##STR19## (e') 1-azabicyclo 3.2.1!octane prepared according to B. Thillet al., J. Org. Chem., 1968, (33), 12, 4376-80. ##STR20## (f')1-azabicyclo 3.2.2!nonane prepared according to C. Ruggles et al., J.Am. Chem. Soc., 1988, (110), 17, 5692-8. ##STR21## (g') 1-azabicyclo3.3.1!nonane prepared according to S. Miyano et al., J. Chem. Soc.,Perkin Trans. 1, 1988, 5, 1057-63. ##STR22## (h')hexahydro-1H-pyrrolizine-4 prepared according to P. Edwards et al.,Tetrahedron Letters, 1984, (25), 9, 939-42. ##STR23## (i')octahydroindolizine-4 prepared according to J. Chastanet et al., J. Org.Chem., 1985, (50), 16, 2910-14. ##STR24## (j')octahydro-2H-quinolizine-5 prepared according to P. Edwards et al.,Tetrahedron Letters, 1984, (25), 9, 939-42. ##STR25## (k') 1-azatricyclo3.3.1.1³,7 !decane or 1-azaadamantane prepared according to Y. Bubnov etal., J. Organomet. Chem., 1991, 412, (1-2), 1-8. ##STR26## (l')4-phenyl-1-azabicyclo 2.2.2!octane or 4-phenylquinuclidine preparedaccording to T. Perrine, J. Org. Chem., 1957, 22, 1484-1489. ##STR27##

The compounds of formula (I) above also include those in which one ormore hydrogen or carbon atoms have been replaced with their radioactiveisotope, for example tritium or carbon-14. Such labeled compounds areuseful in research, metabolic or pharmacokinetic work and in biochemicaltests as receptor ligands.

The compounds according to the invention were subjected to biochemicaltests.

The compounds (I) showed antagonistic properties towards the binding ofsubstance P in tests performed on rat cortex membranes and IM9lymphoblastic cells according to M. A. Cascieri et al., J. Biol. Chem.,1983, 258, 5158-5164, and D. D. Paya et al., J. Immunol., 1984, 133,3260-3265.

Among the compounds tested, (+)-1- 2- 3-(3,4-dichlorophenyl)-1-(3-isopropoxyphenyl)acetyl!piperidin-3-yl!ethyl!-4-phenyl-1-azoniabicyclo2.2.2!octane chloride (compound 4) proved to be a potent antagonist ofthe NK1 receptor of substance P: it inhibits the binding of substance Pto its receptor with an inhibition constant (Ki) of 10-20 pM in thevarious biochemical tests performed.

In particular, the compounds of the present invention are activeprinciples of pharmaceutical compositions, whose toxicity is compatiblewith their use as drugs.

The compounds of formula (I) above can be used in daily doses of 0.01 to100 mg per kilogram of body weight of the mammal to be treated,preferably in daily doses of 0.1 to 50 mg/kg. In humans, the dose canpreferably vary from 0.5 to 4000 mg per day, more particularly from 2.5to 1000 mg per day, depending on the age of the subject to be treated orthe type of treatment: prophylactic or curative.

For their use as drugs, the compounds of formula (I) are generallyadministered in dosage units. Said dosage units are preferablyformulated as pharmaceutical compositions in which the active principleis mixed with a pharmaceutical excipient.

Thus, according to another feature, the present invention relates topharmaceutical compositions in which a compound of formula (I) ispresent as the active principle.

In the pharmaceutical compositions of the present invention for oral,sublingual, subcutaneous, intramuscular, intravenous, transdermal, localor rectal administration, the active principles can be administered toanimals and humans in unit forms of administration, mixed withconventional pharmaceutical carriers. The appropriate unit forms ofadministration include oral forms such as tablets, gelatin capsules,powders, granules and solutions or suspensions to be taken orally,sublingual and buccal forms of administration, subcutaneous,intramuscular, intravenous, intranasal or intraocular forms ofadministration and rectal forms of administration.

When a solid composition in the form of tablets is prepared, the mainactive principle is mixed with a pharmaceutical vehicle such as gelatin,starch, lactose, magnesium stearate, talc, gum arabic or the like. Thetablets can be coated with sucrose or other appropriate substances orelse they can be treated so as to have a prolonged or delayed activityand so as to release a predetermined amount of active principlecontinuously.

A preparation in the form of gelatin capsules is obtained by mixing theactive principle with a diluent and pouring the mixture obtained intosoft or hard gelatin capsules.

A preparation in the form of a syrup or elixir can contain the activeprinciple together with a sweetener, which is preferably calorie-free,methylparaben and propylparaben as antiseptics, a flavoring and anappropriate color.

The water-dispersible granules or powders can contain the activeprinciple mixed with dispersants or wetting agents or with suspendingagents such as polyvinylpyrrolidone, as well as with sweeteners or tastecorrectors.

Rectal administration is effected using suppositories, which areprepared with binders melting at the rectal temperature, for examplecacao butter or polyethylene glycols.

Parenteral, intranasal or intraocular administration is effected usingaqueous suspensions, isotonic saline solutions or sterile and injectablesolutions which contain pharmacologically compatible dispersants and/orwetting agents, for example propylene glycol or butylene glycol.

Administration by inhalation is effected using an aerosol which containsfor example sorbitan trioleate or oleic acid, as well astrichlorofluoromethane, dichlorofluoromethane, dichlorotetrafluoroethaneor any other biologically compatible propellant gas.

The active principle can also be formulated as microcapsules, with oneor more carriers or additives if appropriate.

In each dosage unit, the active principle of formula (I) is present inthe amounts appropriate to the daily doses envisaged. In general, eachdosage unit is suitably adjusted according to the dosage and theintended type of administration, for example tablets, gelatin capsulesand the like, sachets, ampoules, syrups and the like, and drops, so thatsuch a dosage unit contains from 0.5 to 1000 mg of active principle,preferably from 2.5 to 250 mg, to be administered one to four times aday.

According to another feature, the present invention relates to the useof the products of formula (I) for the preparation of drugs intended forthe treatment of physiological disorders associated with an excess oftachykinins, especially substance P, and all the tachykinin-dependentpathologies of the respiratory, gastrointestinal, urinary, immune orcardiovascular system and of the central nervous system as well as painand migraine.

For example without however implying a limitation:

sharp and chronic pains induced for example by migraine, by the pains ofthe cancer and angina patient, by chronic inflammatory processes such asosteoarthritis and rheumatoid arthritis,

inflammations such as obstruent chronic respiratory diseases, asthma,allergies, rhinites, over-sensitiveness such as pollen or acaridaover-sensitiveness, rheumatoid arthrites, osteoarthrites, psoriasis,ulcerative colites, Crohn's disease, inflammation of the intestines(irritable colon), prostatitis, neurological bladder, cystitis,urethritis, nephritis,

complaints of the immune system induced by the deletion or thestimulation of the functions of the immune cells for example rheumatoidarthritis, psoriasis, Crohn's disease, diabetes, lupus,

complaints of the central nervous system such as anxiety, depression,psychotic states, schizophrenia, mania, dementia, epilepsy, Parkinson'sdisease, Alzheimer's disease, drug-dependency, Down's syndrome andHuntington's chorea as well as the neurodegenerative diseases,

complaints of the gastrointestinal system such as nausea, irritablecolon, gastric and duodenal ulcers, diarrheas, hypersecretions,

complaints of the cardiovascular system such as the vascular aspects ofmigraine, oedemas, thrombosis, angina and vascular spasms.

The present invention also includes a method of treating said complaintsat the doses indicated above.

The Examples which follow illustrate the invention without howeverimplying a limitation.

The melting points of the products, m.p., were measured on a Kofflerheating bench.

PREPARATIONS

A. AMINO ALCOHOLS (VII) and (VII*)

PREPARATION I: Scheme 1--Route A

(a) α-(2-Tetrahydropyranyloxyethyl)-3,4-dichlorobenzeneacetonitrile

16.5 g of an 80% dispersion of sodium hydride in oil are suspended in200 ml of dry tetrahydrofuran. A solution of 100 g of3,4-dichlorophenylacetonitrile in 500 ml of tetrahydrofuran is addeddropwise at 20° C. over 30 minutes and the reaction mixture is thenstirred at room temperature for 2 hours. The mixture is cooled to -20°C., a solution of 118 g of 1-bromo-2-tetrahydropyranyloxyethane in 100ml of tetrahydrofuran is added, the mixture is allowed to warm up toroom temperature and, after 2 hours, a solution of 50 g of ammoniumchloride in 3 liters of water is added. Extraction is carried out with1.5 liters of ether and the extract is washed with a saturated solutionof NaCl, decanted, dried over MgSO₄ and concentrated under vacuum. Theresidue is chromatographed on silica gel using CH₂ Cl₂ and then ethylacetate (95/5 v/v) as the eluent. The pure product fractions areconcentrated under vacuum to give 118 g of an oil.

(b) 2-(2-Tetrahydropyranyloxyethyl)-3,4-dichlorobenzeneethanamine

118 g of the nitrile obtained above are dissolved in 700 ml of absoluteethanol. 300 ml of concentrated aqueous ammonia are added, after whichRaney nickel (10% of the amount of starting nitrile) is added whilesweeping with nitrogen. Hydrogenation is then carried out under ahydrogen atmosphere at room temperature and ordinary pressure. 16 litersare absorbed in 4 hours. The catalyst is filtered off on Celite, thefiltrate is concentrated under vacuum and the residue is taken up in asaturated solution of NaCl. After extraction with ether and drying overMgSO₄, 112 g of an oil are obtained.

(c) 2-(2-Hydroxyethyl)-3,4-dichlorobenzeneethanamine

81 g of the product obtained above according to (b) are dissolved in 38ml of methanol. 80 ml of a saturated solution of hydrogen chloride inether are added, the temperature being kept between 20° and 25° C. Themixture is stirred for 30 minutes at room temperature and thenconcentrated to dryness. The residue is dissolved in 250 ml of water,washed twice with ethyl ether, rendered alkaline with a solution of NaOHand extracted with CH₂ Cl₂. After drying over MgSO₄, the extract isconcentrated to dryness, the residue is taken up in 800 ml of isopropylether, an insoluble material is filtered off on Celite, the filtrate isconcentrated under vacuum to about 300 ml and seeded with crystals ofamino alcohol and the mixture is stirred overnight. The crystals arefiltered off and rinsed with isopropyl ether and then with n-pentane togive 30.2 g of the expected product. M.p. =90°-91° C.

(d) 2-(2-Hydroxyethyl)-3,4-dichlorobenzeneethanamine (+)

A solution of 44.7 g of the product obtained according to step (c) abovein 300 ml of methanol is added to a boiling solution of 29 g ofD(-)-tartaric acid in 800 ml of methanol. The mixture is allowed to coolto room temperature and stirred for 4 hours. The product is filtered offand rinsed with ethanol and then ether to give 34.1 g of tartrate. Thisis recrystallized from 1.75 l of methanol to give 26.6 g of tartrate.

α!_(D) ²⁵ =-4.2° (c=1, in H₂ O)

The tartrate is taken up in 120 ml of water, rendered alkaline with asolution of NaOH and extracted twice with CH₂ Cl₂ and the extract isdried over MgSO₄ and concentrated to dryness. The residue is taken up ina small quantity of isopropyl ether, n-pentane is added and the mixtureis filtered to give 15.4 g of product. M.p.=79°-80° C.

α!_(D) ²⁵ =+9.4° (c=1, in CH₃ OH)

(e) N-Methyl-2-(2-hydroxyethyl)-3,4-dichlorobenzeneethanamine (+)hydrochloride

(e1) Ethyl N- 4-(2-hydroxyethyl)-2-(3,4-dichlorophenyl)butyl!carbamate

15 g of the product obtained according to step (d) above are dissolvedin 200 ml of CH₂ Cl₂. 9.9 ml of triethylamine are added. The mixture iscooled to 0° C. and a solution of 6.3 ml of ethyl chloroformate in 30 mlof CH₂ Cl₂ is added dropwise at this temperature. After 15 minutes, themixture is washed with water, then with a dilute solution of HCl andthen with a saturated aqueous solution of NaHCO₃. After drying overMgSO₄, it is concentrated to dryness to give 20 g of product in the formof an oil.

(e2) Reduction of the ethoxycarbonyl group to a methyl group

A solution of 20 g of the product obtained according to step (e1) abovein 150 ml of anhydrous THF is added to 5.1 g of a suspension of lithiumaluminum hydride in 60 ml of anhydrous THF. The mixture is refluxed for1 hour. It is hydrolyzed with 20 ml of water, the inorganic material isfiltered off and the filtrate is concentrated to dryness. The oilobtained is dissolved in 100 ml of acetone. A saturated solution ofhydrogen chloride in ether is added until the pH is 1, after which etheris added until turbidity appears. The mixture is stirred for 1 hour andthe crystals are filtered off and rinsed with a small quantity ofacetone and then with ether to give 11 g ofN-methyl-2-(2-hydroxyethyl)-3,4-dichlorobenzeneethanamine hydrochloride.M.p.=129° C.

α!_(D) ²⁵ =+8.4° (c=1, in CH₃ OH)

(f) N-Methyl-2-(2-hydroxyethyl)-3,4-dichlorobenzeneethanamine (-)hydrochloride

The (-) enantiomer is obtained by following the above procedure startingfrom L(+)-tartaric acid. M.p.=129° C.

α!_(D) ²⁰ =-8.4° (c=1, in CH₃ OH)

PREPARATION II: Scheme 1--Route B, m=1

(a) 3,4-Dichloro-α-(2-tetrahydropyranyloxyethyl)benzeneacetonitrile

20 g of a 55-60% dispersion of sodium hydride in oil are suspended in200 ml of dry tetrahydrofuran. A solution of 85 g of3,4-dichlorophenylacetonitrile in 500 ml of tetrahydrofuran is addeddropwise at 20° C. over 30 minutes and the reaction mixture is thenstirred at room temperature for 2 hours. A solution of 98 g of2-bromoethoxytetrahydropyran in 100 ml of tetrahydrofuran is added tothe resulting mixture cooled to -20° C., the mixture is allowed to warmup to room temperature and, after 2 hours, a solution of 50 g ofammonium chloride in 3 liters of water is added. Extraction is carriedout with 1.5 liters of ethyl ether and the extract is washed with asaturated solution of sodium chloride, decanted, dried over MgSO₄ andconcentrated under vacuum. The residue is chromatographed on silica gelusing dichloromethane as the eluent. The pure product fractions areconcentrated under vacuum to give 83.6 g of an oil.

(b) Ethylβ-tetrahydropyranyloxyethyl-β-cyano-β-(3,4-dichlorophenyl)propionate

21 g of the nitrile prepared above according to (a) are dissolved in 100ml of tetrahydrofuran, a solution of 0.067 mol of lithiumdiisopropylamide in 100 ml of tetrahydrofuran is then added dropwise atroom temperature and the reaction mixture is stirred for one hour atroom temperature. 12 g of ethyl bromoacetate are then added and themixture is heated at 50° C. for two hours. The mixture is cooled, pouredinto a saturated solution of ammonium chloride and extracted with ethylether, the extract is washed with water and the ether phase is separatedoff by decantation, dried over Na₂ SO₄ and concentrated under vacuum.The residue is purified by chromatography on silica gel usingdichloromethane/ethyl acetate (100/1 v/v) as the eluent. Concentrationof the pure fractions gives 13 g of the expected compound.

(c)4-(2-Tetrahydropyranyloxyethyl)-4-(3,4-dichlorophenyl)-2-pyrrolidone

13 g of the compound prepared above are dissolved in 250 ml of ethanoland 40 ml of aqueous ammonia and are hydrogenated at room temperatureand atmospheric pressure in the presence of Raney nickel. When thetheoretical volume of hydrogen has been absorbed, the mixture isfiltered on Celite and the filtrate is concentrated under vacuum. Theresidue is taken up in water and extracted with ethyl ether and theether phase is then washed with water, dried over MgSO₄ and concentratedunder vacuum to give 8.6 g of the expected product.

(d) 3-(2-Tetrahydropyranyloxyethyl)-3-(3,4-dichlorophenyl)pyrrolidine

3.9 g of the4-(2-tetrahydropyranyloxyethyl)-4-(3,4-dichlorophenyl)-2-pyrrolidoneprepared above are dissolved in 50 ml of tetrahydrofuran and thesolution is added to a suspension of 0.9 g of lithium aluminum hydridein 5 ml of THF heated to 60° C. The reaction mixture is heated for onehour at 60° C. and then cooled. 1 ml of water, 1 ml of 4N sodiumhydroxide and 3 ml of water are added. The inorganic material isfiltered off and the filtrate is concentrated under vacuum. The residueis taken up in ethyl ether, dried over MgSO₄ and concentrated undervacuum to give 3.4 g of the expected product.

(e) 3-(2-Hydroxyethyl)-3-(3,4-dichlorophenyl)pyrrolidine

A solution of hydrogen chloride in ether is added to a solution of 3.4 gof 3-tetrahydropyranyloxyethyl-3-(3,4-dichlorophenyl)pyrrolidine in 20ml of methanol until the pH is 1. The mixture is stirred for half anhour at room temperature and concentrated to dryness, the residue istaken up in water, rendered basic with a solution of sodium hydroxideand extracted with dichloromethane and the extract is washed with asaturated solution of NaCl, dried over Na₂ SO₄ and evaporated to drynessto give an oil. This oil is taken up in 20 ml of an isopropylether/ether mixture (50/50 v/v). After stirring and filtration, theproduct is washed with ethyl ether and dried under vacuum over P₂ O₅.2.6 g of the expected product are isolated.

PREPARATION III: Scheme 1--Route B, m=2

(a) Ethylγ-(2-tetrahydropyranyloxyethyl)-γ-cyano-γ-(3,4-dichlorophenyl)butanoate

21 g of the nitrile prepared according to step (a) above are dissolvedin 100 ml of tetrahydrofuran, a solution of 0.067 mol of lithiumdiisopropylamide in 100 ml of tetrahydrofuran is then added dropwise atroom temperature and the reaction mixture is stirred for one hour atroom temperature. 12 g of ethyl bromopropionate are then added and themixture is heated at 50° C. for two hours. The mixture is cooled, pouredinto a saturated solution of ammonium chloride and extracted with ether,the extract is washed with water and the ether phase is separated off bydecantation, dried over Na₂ SO₄ and concentrated under vacuum. Theresidue is purified by chromatography on silica gel usingdichloromethane/ethyl acetate (100/1 v/v) as the eluent. Concentrationof the pure fractions gives 13 g of the expected compound.

(b)5-(2-Tetrahydropyranyloxyethyl)-5-(3,4-dichlorophenyl)-2-piperidinone

13 g of the compound prepared above are dissolved in 250 ml of ethanoland 40 ml of aqueous ammonia and are hydrogenated at room temperatureand atmospheric pressure in the presence of Raney nickel. When thetheoretical volume of hydrogen has been absorbed, the mixture isfiltered on Celite and the filtrate is concentrated under vacuum. Theresidue is taken up in water and extracted with ether and the etherphase is then washed with water, dried over MgSO₄ and concentrated undervacuum to give 9 g of the expected product.

(c) 3-(2-Tetrahydropyranyloxyethyl)-3-(3,4-dichlorophenyl)piperidine

3.9 g of the5-(2-tetrahydropyranyloxyethyl)-5-(3,4-dichlorophenyl)piperidinoneprepared above are dissolved in 50 ml of tetrahydrofuran and thesolution is added to a suspension of 0.9 g of lithium aluminum hydridein 5 ml of THF heated to 60° C. The reaction mixture is heated for onehour at 60° C. and then cooled. 1 ml of water, 1 ml of 4N sodiumhydroxide and 3 ml of water are added. The insoluble portion is filteredoff and the filtrate is concentrated under vacuum. The residue is takenup in ethyl ether, dried over MgSO₄ and concentrated under vacuum togive 3.4 g of the expected product.

(d) 3-(2-Hydroxyethyl)-3-(3,4-dichlorophenyl)piperidine

A saturated solution of hydrogen chloride in ether is added to asolution of 55 g of3-(2-tetrahydropyranyloxyethyl)-3-(3,4-dichlorophenyl)piperidine in 200ml of methanol until the pH is 1. The mixture is stirred for half anhour at room temperature and concentrated to dryness, the residue istaken up in water, rendered alkaline with a solution of NaOH andextracted with CH₂ Cl₂ and the extract is washed with a saturatedsolution of NaCl, dried over Na₂ SO₄ and evaporated to dryness to givean oil. This oil is taken up in 200 ml of an isopropyl ether/ethermixture (50/50 v/v). After stirring and filtration, the product iswashed with ethyl ether and dried under vacuum over P₂ O₅ to give 45 gof the expected product. M.p.=122° C.

(e) 3-(2-Hydroxyethyl)-3-(3,4-dichlorophenyl)piperidine (+)

A solution of 23.54 g of L(+)-tartaric acid in 750 ml of 100° ethanol isadded to a refluxing solution of 43 g of the product obtained above in250 ml of 100° ethanol. The reaction mixture is refluxed for half anhour and allowed to cool to room temperature and the crystals obtainedare filtered off, washed with 100° ethanol and dried under vacuum at 50°C. over P₂ O₅ to give 31 g of tartrate. After recrystallization from 540ml of 100° ethanol and filtration, the tartrate is washed with ethylether and dried under vacuum over P₂ O₅ to give 25 g of tartrate.

α!_(D) ²⁰ =+8.5° (c=1, in H₂ O)

The tartrate is then taken up in water, neutralized with a solution ofNaOH and extracted with CH₂ Cl₂ and the extract is washed with water,dried over Na₂ SO₄ and evaporated to dryness. The oil is taken up in anethyl ether/isopropyl ether mixture and the crystals are filtered off,washed with ethyl ether and dried under vacuum at 50° C. to give 13.5 gof base. M.p.=138° C.

α!_(D) ²⁰ =+8.2° (c=1, in CH₃ OH)

(f) 3-(2-Hydroxyethyl)-3-(3,4-dichlorophenyl)piperidine (-)

The (-) enantiomer is obtained by following the above procedure startingfrom D(-)-tartaric acid. M.p.=139° C.

α!_(D) ²⁰ =-8.4° (c=1, in CH₃ OH)

PREPARATION IV: Scheme 1--Route B, m=3

(a) Ethylδ-(2-tetrahydropyranyloxyethyl)-δ-cyano-δ-(3,4-dichlorophenyl)pentanoate

4.6 g of 60% NaH are added in small portions to a solution of 36 g ofthe above 3,4-dichloro-α-(2-tetrahydropyranyloxy)ethyl!benzeneacetonitrile (prepared according toPREPARATION II (a)) in 100 ml of dimethylformamide. The reaction mixtureis stirred for 3 hours at room temperature and cooled to 0° C. and 22.4g of ethyl 4-bromobutyrate in 40 ml of dimethylformamide are then added.The reaction mixture is stirred for 3 hours at room temperature, pouredinto water and extracted with ether and the extract is washed with asaturated solution of NaCl, dried over Na₂ SO₄ and concentrated undervacuum. The residue obtained is purified by chromatography on silica gelusing toluene as the eluent to give 24 g of the expected product.

(b)6-(2-Tetrahydropyranyloxyethyl)-6-(3,4-dichlorophenyl)perihydro-2-azepinone

8 g of the product obtained above, dissolved in 120 ml of ethanol, arehydrogenated at atmospheric pressure and room temperature in thepresence of Raney nickel. When the theoretical volume of hydrogen hasbeen consumed, the catalyst is filtered off and the filtrate isconcentrated under vacuum. The oil obtained is then taken up in 20 ml ofxylene and the reaction mixture is refluxed for 48 hours. It isevaporated and the residue obtained is purified by chromatography onsilica gel using CH₂ Cl₂ /CH₃ OH (100/1 v/v) as the eluent to give 4 gof the expected product in the form of an oil.

(c)3-(2-Tetrahydropyranyloxyethyl)-3-(3,4-dichlorophenyl)perihydroazepine

1.7 g of the expected product are obtained in the form of an oil byfollowing the previous preparation, step (d), starting from 2 g of theproduct obtained above and 0.49 g of lithium aluminum hydride.

(d) 3-(2-Hydroxyethyl)-3-(3,4-dichlorophenyl)perhydroazepine

1.3 g of the expected product are obtained by following the previouspreparation, step (e), starting from 1.7 g of the product obtainedabove.

B. SUBSTITUTED PHENYLACETIC ACIDS

3-chlorophenylacetic acid and 3-ditrifluoromethylphenylacetic acid arecommercially available.

B1. 3-ISOPROPOXYPHENYLACETIC ACID PREPARATION V. 1

3-Isopropoxyphenylacetic acid is not known in the literature but can beprepared by well-known methods of preparing alkoxyphenylacetic acids.

(a) Ethyl 3-hydroxyphenylacetate

A solution of 55 g of 3-hydroxyphenylacetic acid in 400 ml of 100°ethanol is refluxed overnight in the presence of a few drops ofconcentrated H2SO₄. It is evaporated to dryness and the residue is takenup in ethyl ether and washed with water and then with a saturatedaqueous solution of NaHCO₃. After drying over MgSO₄ followed byevaporation, 58 g of an oil are obtained.

(b) Ethyl 3-isopropoxyphenylacetate

A solution of 58 g of the product obtained above, 88 g of K₂ CO₃ and 108g of 2-iodopropane in 300 ml of DMF is heated at 80°-100° C. for 8hours. The DMF is evaporated off under vacuum and the residue is takenup in ethyl acetate and washed with a 10% aqueous solution of K₂ CO₃.After drying over MgSO₄ followed by evaporation, the residue is purifiedby chromatography on silica gel using CH₂ Cl₂ as the eluent to give 61 gof an oil.

(c) 3-Isopropoxyphenylacetic acid

A solution of 31 g of the product obtained above and 20 g of NaOH in 400ml of ethanol is refluxed for 2 hours. It is evaporated to dryness andthe residue is taken up in water and acidified with concentrated HCl.Extraction is carried out with ethyl ether and the extract is washedwith water, dried over MgSO₄ and concentrated to dryness to give 27 g ofthe expected acid. M.p.=33°-35° C.

B2. 2-IODO-5-ISOPROPOXYPHENYLACETIC ACID PREPARATION V. 2

2-iodo-5-isopropoxyphenylacetic acid is not known in the literature butcan be prepared by known methods for example according to R. E. Counselet al., J. Med. Chem., 1973, 16, 6, 684-687 by replacing the benzylchloride with the 2-iodopropane.

15 g of the thus prepared 2-iodo-5-isopropoxyphenylacetonitrile aredissolved in 160 ml of ethanol in the presence of 18 g of KOH and thenthe mixture is refluxed for two hours. It is concentrated under vacuumand the residue is taken up in water and successively it is washed withethyl ether, the aqueous phase is acified by adding HCl until the pH is1 and extracted with ethyl ether and the extract is washed with water,dried over Na₂ SO₄ and filtered. It is concentrated under vacuum and theresidue is purified by chromatography on silica gel using CH₂ Cl₂ --CH₃OH (100-2 v/v) as the eluent to give after concentration of the purefractions, 8 g of the expected acid in the form of an oil. NMR Spectrum(200 MHz): 1.2 ppm--2CH₃ ; 3.5 ppm--1CH₂ ; 4.6 ppm--1CH; 6.6 ppm--1Haromatic; 6.9 ppm--1H aromatic; 7.6 ppm--1H aromatic.

C. ACYL DERIVATIVES (VI) AND SULFONYLOXY DERIVATIVES (II)

PREPARATION VI: Scheme 1--Route B, m=1

(a)3-(2-Hydroxyethyl)-3-(3,4-dichlorophenyl)-1-(3-isopropoxyphenyl)acetylpyrrolidine

2.25 ml of triethylamine and then 2.6 g of the3-(2-hydroxyethyl)-3-(3,4-dichlorophenyl)pyrrolidine prepared above areadded to a solution of 1.9 g of 3-isopropoxyphenylacetic acid in 50 mlof CH₂ Cl₂. The mixture is cooled to 0° C., 4.42 g of BOP are then addedand the reaction mixture is allowed to warm up to room temperature.After 30 minutes, the mixture is concentrated under vacuum and theresidue is taken up in ethyl ether and washed successively with water, adilute solution of NaOH, a saturated solution of NaCl, a dilute solutionof HCl, a saturated solution of NaCl and a solution of NaHCO₃. The etherphase is dried over MgSO₄, filtered and concentrated under vacuum togive 3.6 g of the expected product.

(b)3-(2-Methanesulfonyloxyethyl)-3-(3,4-dichlorophenyl)-1-(3-isopropoxyphenyl)acetylpyrrolidine

2.2 g of the product prepared above are dissolved in 50 ml of CH₂ Cl₂and the solution is cooled to 0° C. 1.5 g of triethylamine are added and0.57 g of methanesulfonyl chloride is then added dropwise. The reactionmixture is left to stand for 15 minutes at 0° C. and then concentratedunder vacuum, the residue is taken up in ether and washed with water andthe ether phase is dried over MgSO₄, filtered and concentrated undervacuum. The residue is chromatographed on silica gel using heptane/ethylacetate (50/50 v/v) up to pure ethyl acetate as the eluent. The pureproduct fractions are concentrated under vacuum and the residue is thensolidified in an ethyl ether/isopropyl ether mixture to give 2.5 g ofthe expected product.

PREPARATION VII: Scheme 1--Route B, m=2

(a) Optically pure 3-(2-hydroxyethyl)-3-(3,4-dichlorophenyl)-1-(3-isopropoxyphenyl)acetyl!piperidine

22.5 ml of triethylamine and then 22 g of the3-(2-hydroxyethyl)-3-(3,4-dichlorophenyl)piperidine (-) prepared aboveaccording to PREPARATION III (f) are added to a solution of 16 g of3-isopropoxyphenylacetic acid in 500 ml of CH₂ Cl₂. The mixture iscooled to 0° C., 42.6 g of BOP are then added and the reaction mixtureis allowed to warm up to room temperature. After 30 minutes, the mixtureis concentrated under vacuum and the residue is taken up in ether andwashed successively with water, a dilute solution of NaOH, a saturatedsolution of NaCl, a dilute solution of HCl, a saturated solution of NaCland a solution of NaHCO₃. The ether phase is dried over MgSO₄, filteredand concentrated under vacuum to give 36 g of optically pure product.(+)

(b) 3-(2-Methanesulfonyloxyethyl)-3-(3,4-dichlorophenyl)-1-(3-isopropoxyphenyl)acetyl!piperidine

36 g of the product prepared above are dissolved in 500 ml of CH₂ Cl₂and the solution is cooled to 0° C. 11.5 ml of triethylamine are addedand 6.3 ml of methanesulfonyl chloride are then added dropwise. Thereaction mixture is left to stand for 15 minutes at 0° C. and thenconcentrated under vacuum, the residue is taken up in ether and washedwith water and the ether phase is dried over MgSO₄, filtered andconcentrated under vacuum. The residue is chromatographed on silica gelusing heptane/ethyl acetate (50/50 v/v) up to pure ethyl acetate as theeluent. The pure product fractions are concentrated under vacuum and theresidue is then solidified in an ethyl ether/isopropyl ether mixture togive 37.5 g of the expected product. M.p.=72° C.

α!_(D) ²⁰ =+25.7° (c=1, in CHCl₃)

(c) 3-(2-Benzenesulfonyloxyethyl)-3-(3,4-dichlorophenyl)-1-(3-isopropoxyphenyl)acetyl!piperidine

4.6 ml of triethylamine and then, dropwise, 4.3 ml of benzenesulfonylchloride are added to 11.3 g of the product prepared above according toPREPARATION VII (a) in 160 ml of CH₂ Cl₂ and the solution is cooled to0° C. The reaction mixture is left to stand for 18 hours at roomtemperature and is then successively treated with 100 ml of HCl, 100 mlof 10% Na₂ CO₃ and 100 ml of water. The organic phase is filtered off,dried over Na₂ SO₄ and then concentrated under vacuum. The residue ischromatographed on silica gel using cyclohexane/AcOEt (80/20 v/v) as theeluent. The pure product fractions are concentrated to give 8.4 g of theexpected product.

PREPARATION VIII: Scheme 1--Route B, m=3

(a) 3-(2-Hydroxyethyl)-3-(3,4-dichlorophenyl)-1-(3-isopropoxyphenyl)acetyl!perihydroazepine

1.2 g of triethylamine and then 1.15 g of the3-(2-hydroxyethyl)-3-(3,4-dichlorophenyl)azepine prepared above areadded to a solution of 0.76 g of 3-isopropoxyphenylacetic acid in 50 mlof CH₂ Cl₂. The mixture is cooled to 0° C., 1.77 g of BOP are then addedand the reaction mixture is allowed to warm up to room temperature.After 30 minutes, the mixture is concentrated under vacuum and theresidue is taken up in ethyl ether and washed successively with water, adilute solution of NaOH, a saturated solution of NaCl, a dilute solutionof HCl, a saturated solution of NaCl and a solution of NaHCO₃. The etherphase is dried over MgSO₄, filtered and concentrated under vacuum togive 1.8g.

(b) 3-(2-Methanesulfonyloxyethyl)-3-(3,4-dichlorophenyl)-1-(3-isopropoxyphenyl)acetyl!perihydroazepine.

1.8 g of the product prepared above are dissolved in 50 ml of CH₂ Cl₂and the solution is cooled to 0° C. 0.38 g of triethylamine is added and0.44 g of methanesulfonyl chloride is then added dropwise. The reactionmixture is left to stand for 15 minutes at 0° C. and then concentratedunder vacuum, the residue is taken up in ethyl ether and washed withwater and the ether phase is dried over MgSO₄, filtered and concentratedunder vacuum. The residue is chromatographed on silica gel usingheptane/ethyl acetate (50/50 v/v) up to pure ethyl acetate as theeluent.

The pure product fractions are concentrated under vacuum and the residueis then solidified in an ethyl ether/isopropyl ether mixture to give 2 gof the expected product.

D. AMINE (III)

PREPARATION IX: Scheme 2-4-benzylquinuclidine

(a) 1-benzyl-4-carbamoylpiperidine.

100 g of isonipecotamide are placed in 550 ml of DMF and 127 g ofpotassium carbonate are added. 101 ml of benzyl bromide are then addeddropwise while maintaining the temperature of the reaction mixture at25° C. with an ice bath. The reaction mixture is left to stand one dayat room temperature under stirring and then filtered, the precipitate iswashed several times with DMF and then the organic phases are pooled andevaporated. The precipitate thus formed is extracted with CH₂ Cl₂ andthen washed with water. The organic phase is dried over MgSO₄ andevaporated under vacuum. After recrystallization from water, 101.51 g ofthe expected compound are recovered. M.p=163° C.

(b) 1-benzyl-4-cyanopiperidine.

100 g of the compound obtained in step (a) are dissolved in 334 ml ofphosphoryl chloride, and the mixture is then refluxed during 2 hours.The reaction mixture is concentrated to dryness and 200 ml of tolueneare added. The reaction mixture is again concentrated and poured into 11 of water while maintaining the temperature at 25° C. with an ice bath,and the pH is raised to 10 by addition of 10N NaOH. The reaction mixtureis extracted 3 times with CH₂ Cl₂ and then dried over MgSO₄ andevaporated. The obtained liquid is purified by distillation under apressure of 0.022 millibars at a temperature of 114°-116° C. 86.8 g ofthe expected compound are recovered.

(c) 1,4-dibenzyl-4-cyanopiperidine.

80 g of the compound obtained in step (b) are mixed with 650 ml of THF,and 295 ml of lithium diisopropylamide are added dropwise while thereaction mixture is maintained under nitrogen atmosphere andrefrigerated at -50° C. After 1 h under stirring, 54 ml of benzylbromide are added dropwise and then the temperature of the reactionmixture is allowed to rise to room temperature over 3 hours. Thereaction mixture is then washed with 2 l of a mixture of ammoniumchloride and ice. The product which precipitates is extracted withether, and the organic phase is separated, dried over MgSO₄ evaporatedto dryness, washed with pentane and filtered to give 106.8 g of theexpected compound in the form of a white solid. M.p=92° C.

(d) 4-acetyl-1,4-dibenzylpiperidine chloride.

60 g of the compound obtained in step (c) are dissolved under stirringin 1 l of ether. 165 ml of methyllithium are added dropwise. After 3hours under stirring, the reaction mixture is poured into 1 l of icedwater. The organic phase is separated, dried over MgSO₄ and evaporatedto dryness. The oil formed is refluxed for 2 hours with 1.3 1 of 1M HCland the reaction mixture is left to stand 24 hours at room temperature.The expected product crystallizes in the reaction mixture, and is thenfiltered, wrung, successively washed with acetone and ether and driedunder vacuum at 120° C. to give 59.90 g of the expected compound.M.p=240° C.

(e) 4-bromoacetyl-1,4-dibenzylpiperidine bromide.

58 g of the compound of step (d) are dissolved in 232 ml of acetic acid.9.3 ml of bromine are added under stirring and the reaction mixture ismaintained under stirring for 24 hours at room temperature. The expectedproduct crystallizes in the reaction mixture and 300 ml of ether areadded before filtering the formed compound. After washing with anacetone/ether mixture and then with ether and drying in a drying ovenunder vacuum, 70.6 g of the expected compound are recovered. M.p=200° C.

(f) 1,4-dibenzyl-3-oxoquinuclidinium bromide.

68 g of the compound of step (e) are suspended into 500 ml of water andthe reaction mixture is rendered basic at pH>10 by addition of 10M NaOH.The formed product is extracted with ether, dried over MgSO₄ and thenevaporated to dryness. The formed foam is taken up in 50 ml of acetoneand stirred during 2 hours. The formed crystals are filtered and washedwith ether to give 36.5 g of the expected compound. M.p=226° C.

(g) 4-benzyl-3-oxoquinuclidine.

35.5 g of the compound of step (f) are mixed with 3.6 g of 10 % Pd/C in700 ml of methanol and the mixture is stirred under hydrogen atmosphereat atmospheric pressure. After absorption of 2.2 l of hydrogen, thecatalyst is filtered off on Celite® and the solution is evaporated todryness. The formed crystals are washed with ether and then dried. Thesecrystals are dissolved in the minimum amount of water and the mixture isrendered basic by addition of 10N NaOH until all the amine precipitates.The amine is then filtered, rinsed with iced water and dried undervacuum to give 19.3 g of the expected product in the form of a whitesolid. M.p=110° C.

(h) 4-benzylquinuclidine.

16 g of the compound obtained in step (g) are added to 8 g of hydrazinehydrate and 14 g of KOH in 80 ml of triethyleneglycol. The reactionmixture is refluxed under nitrogen during 1 and a half hours. Afterdistilling the water off, the reaction mixture is heated at 195° C.during 3 hours, poured into 1 l of iced water and extracted twice withether. The ether phases are pooled, dried over MgSO₄ and evaporated todryness. The formed solid is dissolved in the minimum amount of acetoneand the mixture is rendered acid with chlorhydric ether until pH=1. Theformed precipitate is washed several times with ether, filtered, dried,dissolved in the minimum amount of water, rendered basic until pH>10 andextracted twice with ether. The ether solution is dried over MgSO₄ andevaporated to give 10.4 g of the expected compound in the form of awhite solid. M.p=49° C.

EXAMPLE 1 ##STR28##

0.75 g of 4-phenylquinuclidine, synthesized according to T. Perrine, J.Org. Chem., 1957, 22, 1484-1489, and 1 g of N-2-(3,4-dichlorophenyl)-4-methanesulfonyloxybutyl!-N-methyl-(3-isopropoxyphenyl)carboxamide,prepared according to EP-A-0 428 434, are dissolved in 5 ml ofacetonitrile. The reaction mixture is refluxed for 4 hours and thenconcentrated under vacuum. The residue is taken up in CH₂ Cl₂ and thenwashed successively with a 2N solution of HCl and a saturated solutionof NaCl and the organic phase is dried over MgSO₄, filtered andconcentrated under vacuum. The residue is solidified in ethyl ether togive 0.39 g of 1-3-(3,4-dichlorophenyl)-4-(N-methyl-3-isopropoxyphenylacetylamino)butyl!-4-phenyl-1-azoniabicyclo2.2.2!octane chloride (compound 1). M.p.=98°-100° C.

EXAMPLE 2 ##STR29##

The optically pure derivative (-)-1-3-(3,4-dichlorophenyl)-4-(N-methyl-3-isopropoxyphenylacetylamino)butyl!-4-phenyl-1-azoniabicyclo2.2.2!octane chloride (compound 2), m.p.=97°-99° C., is obtained byfollowing the procedure of Example 1 using the optically pure derivative(-)-N-2-(3,4-dichlorophenyl)-4-methanesulfonyloxybutyl!-N-methyl-(3-isopropoxyphenyl)carboxamide,prepared according to EP-A-0 428 434, as the starting material.

α!_(D) ²⁰ =-47.2° (c=1, in CH₃ OH)

EXAMPLE 3 ##STR30##

1-3-(3,4-Dichlorophenyl)-4-(N-methyl-3-isopropoxyphenylacetylamino)butyl!-1-azoniabicyclo2.2.2!-octane chloride (compound 3), m.p.=68°-70° C., is obtained byfollowing the procedure of Example 1 using quinuclidine as the tertiaryamine.

EXAMPLE 4 ##STR31##

2.25 g of 4-phenylquinuclidine and 3.17 g of the mesylate preparedaccording to PREPARATION VII (b) are dissolved in 30 ml of acetonitrileand the reaction mixture is refluxed for 10 hours. The mixture isconcentrated under vacuum and the residue is taken up in CH₂ Cl₂ andwashed successively with a 3N solution of HCl and then a saturatedsolution of NaCl. The organic phase is dried over MgSO₄, filtered andconcentrated under vacuum. The residue precipitates from anacetone/ether mixture to give 2.8 g of optically pure (+)-1- 2-3-(3,4-dichlorophenyl)-1-(3-isopro-poxyphenyl)acetyl!piperidin-3-yl!ethyl!-4-phenyl-1-azoniabicyclo2.2.2!octane chloride (compound 4). M.p.=132° C.

α!_(D) ²⁰ =+16.3° (c=1, in CH₃ OH)

EXAMPLE 5 ##STR32##

2.65 g of 4-phenylquinuclidine and 8.3 g of the benzenesulfonateprepared according to PREPARATION VII (c) are dissolved in 40 ml ofacetonitrile and the reaction mixture is refluxed for 6 hours. Themixture is concentrated under vacuum and the residue is taken up in CH₂Cl₂ and washed successively with a 1% aqueous solution ofbenzenesulfonic acid and then with water. The organic phase is driedover Na₂ SO₄, filtered and concentrated under vacuum. The residueprecipitates from isopropyl ether to give 8 g of optically pure (+)-1-2- 3-(3,4-dichlorophenyl)-1-(3-isopropoxyphenyl)acetyl!piperidin-3-yl!ethyl!-4-phenyl-1-azoniabicyclo2.2.2!octane benzenesulfonate (compound 5). M.p.=195.5° C.

α!_(D) ²⁰ =-50.7° (c=1, in CH₃ OH)

Compounds 6 to 12 described in TABLES I and II below are prepared byfollowing

EXAMPLES 1 to 5.

                                      TABLE I                                     __________________________________________________________________________     ##STR33##                                                                                                     M.p.;                                                                         in °C.                                Example                          and/or                                       n°                                                                          Ar'       R  T    Ar         α!.sub.D *                            __________________________________________________________________________          ##STR34##                                                                              CH.sub.3                                                                         --                                                                                  ##STR35##                                                                              150 -57.9°                            7                                                                                   ##STR36##                                                                              CH.sub.3                                                                         --                                                                                  ##STR37##                                                                              178                                          8                                                                                   ##STR38##                                                                              CH.sub.3                                                                         CH.sub.2                                                                            ##STR39##                                                                              97                                           9                                                                                   ##STR40##                                                                              H  --                                                                                  ##STR41##                                                                              104-106                                      __________________________________________________________________________     *The rotary powers,  α!.sub.D, were measured at 20° C., c =      in CH.sub.3 OH.                                                          

                  TABLE II                                                        ______________________________________                                         ##STR42##                                                                                                      M.p.; °C.                            Example n°                                                                        Ar           A.sup.⊖                                                                         and/or  α!.sub.D                      ______________________________________                                        10                                                                                        ##STR43##   Cl.sup.⊖                                                                        125; -16.0°                          11                                                                                        ##STR44##   Br.sup.⊖                                                                        196-198                                     12                                                                                        ##STR45##   Cl.sup.⊖                                                                        156-160 +11.0°                       ______________________________________                                    

EXAMPLE 13 ##STR46##

8,2 g of ethyloxalyl chloride are added dropwise to a solution of 19 gof 2-(2-tetrahydropyranyloxyethyl)-3,4-dichlorobenzeneethanamine(obtained according to PREPARATION (I)--Step (b)) and of 7 g oftriethylamine. The reaction mixture is stirred for one hour at roomtemperature and concentrated under vacuum. The residue is taken up inethyl ether and is successively washed with water, dried over Na₂ SO₄and concentrated under vacuum. The residue is chromatographed on silicagel using CH₂ Cl₂ /CH₃ OH (100/1 v/v) as the eluent to give 16 g ofN-ethyloxalyl-2-(2-tetrahydropyranyloxyethyl)-3,4-dichlorobenzeneethanamine.

Step 2

16 g of the product obtained above are dissolved in 40 ml of THF andadded dropwise to a suspension of 1.7 g of LiAlH₄ in 5 ml of THF at 50°C. The reaction mixture is refluxed for 4 hours, cooled, hydrolyzed,filtered and concentrated under vacuum. The residue is chromatographedon silica gel using CH₂ Cl₂ /CH₃ OH (100/5 v/v) as the eluent to give 14g ofN-(2-hydroxyethyl)-2-(2-tetrahydropyranyloxyethyl)-3,4-dichlorobenzeneethanamineunder the form of an oil.

Step 3

3.55 g of BOP are added at 0° C. to a solution of 2.4 g of the productprepared above, 1.1 g of triethylamine and 1.3 g of3-isopropoxyphenylacetic acid in 60 ml of CH₂ Cl₂. The reaction mixtureis stirred for one hour at 0° C. and is then successively concentratedunder vacuum, taken up in AcOET, washed with water, dried over Na₂ SO₄and concentrated under vacuum. The residue is chromatographed on silicagel using CH₂ Cl₂ /CH₃ OH (100/3 v/v) as the eluent to give 2.2 g ofN-(2-hydroxyethyl)-N-(3-isopropoxyphenylacetyl)-2-(2-tetrahydropyranyloxyethyl)-3,4-dichlorobenzeneethanamineunder the form of an oil.

Step 4

0.41 g of acetyl chloride is added to a solution of 2.2 g of the productobtained above in 10 ml of CH₂ Cl₂ in the presence of 0.56 g oftriethylamine in CH₂ Cl₂. The reaction mixture is stirred for one hourand is then successively concentrated under vacuum, washed with ethylether, with water, dried over Na₂ SO₄ and concentrated under vacuum togive 2 g ofN-(2-acetoxyethyl)-N-(3-isopropoxyphenylacetyl)-2-(2-tetrahydropyranyloxyethyl)-3,4-dichlorobenzeneethanamine under the form of an oil.

Step 5

2 g of the oil obtained above are dissolved in 20 ml of methanolsaturated with HCl and the mixture is stirred for one hour at roomtemperature. The reaction mixture is concentrated under vacuum, theresidue is taken up in AcOET, washed with water, dried over Na₂ SO₄ andchromatographed on silica gel using CH₂ Cl₂ /CH₃ OH (100/3 v/v) as theeluent to give 1.2 g ofN-(2-acetoxyethyl)-N-(3-isopropoxyphenylacetyl)-2-hydroxyethyl-3,4-dichlorobenzeneethanamineunder the form of an oil.

Step 6

0.5 g of the product prepared above is dissolved in 10 ml of CH₂ Cl₂ inthe presence of 0.11 g of triethylamine. 0.125 g of mesyl chloride isadded and the reaction mixture is stirred for 30 minutes at roomtemperature. The reaction mixture is concentrated under vacuum and thenthe residue is successively taken up in AcOET, washed with water, driedover Na₂ SO₄ and concentrated under vacuum to give 0.5 g ofN-(2-acetoxyethyl)-N-(3-isopropoxyphenylacetyl)-2-mesyloxyethyl-3,4-dichlorobenzeneethanamineunder the form of an oil.

Step 7

0.5 g of the product prepared above and 0.25 g of 4-phenylquinuclidineare dissolved in 1 ml of dimethylformamide and the reaction mixture isheated at 80° C. for two hours. The reaction mixture is poured intowater and then successively extracted with AcOET, washed with water,with a saturated solution of NaCl, concentrated under vacuum and theresidue is chromatographed on silica gel using CH₂ Cl₂ /CH₃ OH (100/5v/v) as the eluent. The pure fractions are concentrated under vacuum,the residue is taken up in CH₂ Cl₂ and precipitated by adding ethylether to give 0.45 g of 1-3-(3,4-dichlorophenyl)-4-(N-(2-acetoxyethyl)-3-isopropoxyphenylacetylamino)butyl!-1-azoniabicyclo2.2.2.!octane chloride (Compound 13). M.p.=90°-92° C.

EXAMPLE 14

1- 3-(3,4-dichlorophenyl)-4-N-(2-methoxyethyl)-3-isopropoxyphenylacetamido!-butyl!-4-phenyl-1-azoniabicyclo2.2.2.!octane chloride ##STR47## Step 1N-methoxyacetyl-2-(3,4-dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butylamine

A mixture of 8.6 g of2-(3,4-dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butylamine (obtainedaccording to PREPARATION (I), step (b)), 2.46 g of methoxyacetic acid,5.55 g of triethylamine in 50 ml of dichloromethane is cooled to 0° C.and 14.5 g of BOP is added thereto. The reaction mixture is stirred forone hour at room temperature and concentrated under vacuum. The residueis taken up in ethyl acetate and is successively washed with water,dried over Na₂ SO₄ and concentrated under vacuum. The residue ischromatographed on silica gel using CH₂ Cl₂ /CH₃ OH (100/1 v/v) as theeluent to give 7.5 g of the expected product.

Step 2

N-(2-methoxyethyl)-2-(3,4-dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butylamine

A suspension of 1.5 g of LiAlH₄ in 30 ml of tetrahydrofuran (THF) isrefluxed and a solution of 7.5 g of the product obtained in step 1 in 40ml of THF are added dropwise thereto.

The reaction mixture is refluxed for 3 hours, cooled, hydrolyzed,filtered and the filtrate is concentrated under vacuum. The residue ischromatographed on silica gel using CH₂ Cl₂ /CH₃ OH (100/5 v/v) as theeluent to give 4.1 g of the expected product.

Step 3

N-(3-isopropoxyphenylacetyl)-N-(2-methoxyethyl)-2-(3,4-dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butylamine

2.6 g of BOP are added to a solution cooled at 0° C. of 1.9 g of theproduct prepared in step 2, 1.2 g of triethylamine and 0.96 g of3-isopropoxyphenylacetic acid in 50 ml of CH₂ Cl₂. The reaction mixtureis stirred for one hour and is then concentrated under vacuum. Theresidue is taken up in ethyl acetate, washed with water, dried over Na₂SO₄ and concentrated under vacuum. 2.2 g of the expected product isobtained, which is directly used in the next step.

Step 4

N-(3-isopropoxyphenylacetyl)-N-(2-methoxyethyl)-2-(3,4-dichlorophenyl)-4-hydroxybutylamine

A saturated solution of hydrochloric acid in diethylether is added to asolution of 2.2 g of the product obtained in step 3 in 30 ml ofmethanol, until the obtention of a pH value of 1.

The reaction mixture is stirred at ambient temperature for 30 min. andis then concentrated under vacuum. The residue is taken up with ethylacetate, washed with water, dried over Na₂ SO₄ and concentrated undervacuum to give 1.8 g of the expected product which is directly used inthe next step.

Step 5

N-(3-isopropoxyphenylacetyl)-N-(2-methoxyethyl)-2-(3,4-dichlorophenyl)-4-mesyloxybutylamine

0.526 g of methanesulfonyl chloride are added to a mixture of 1.8 g ofthe product obtained in step 4 and 0.46 g of triethylamine in 40 ml ofdichloromethane. The reaction mixture is stirred at ambient temperaturefor 1 h and is then concentrated under vacuum. The residue is taken upwith ethyl acetate, washed with water, dried over Na₂ SO₄ andconcentrated under vacuum to give 2 g of the expected product.

Step 6

1- 3-(3,4-dichlorophenyl)-4-N-(2-methoxyethyl)-3-isopropoxyphenylacetamido!-butyl!-4-phenyl-1-azoniabicyclo2.2.2!octane chloride

2 g of the product prepared in step 5 and 1 g of 4-phenylquinuclidineare dissolved in 2 ml of dimethylformamide and the reaction mixture isheated at 80° C. for 4 hours. After cooling, the reaction mixture ispoured into water and then successively extracted with ethyl acetate,washed with a 5% solution of hydrochloric acid, with a saturatedsolution of NaCl, dried over Na₂ SO₄ and concentrated under vacuum.

The residue is chromatographed on silica gel using CH₂ Cl₂ /CH₃ OH(100/1 v/v) as the eluent. 0.9 g of the expected compound are obtained.M.P.=85°-88° C.

Compounds 15 to 22 described in TABLE III below are prepared byfollowing the methods described above.

                                      TABLE III                                   __________________________________________________________________________     ##STR48##                                                                    Example                                                                            Ar        T    Ar'     RQ    Am.sup.+ A.sup.-  M.p                       __________________________________________________________________________                                                        °C./NMR            15                                                                                  ##STR49##                                                                              CH.sub.2                                                                            ##STR50##                                                                            (CH.sub.2).sub.3                                                                     ##STR51##        122                       16                                                                                  ##STR52##                                                                              CH.sub.2                                                                            ##STR53##                                                                            (CH.sub.2).sub.4                                                                     ##STR54##        115                       17                                                                                  ##STR55##                                                                              CH.sub.2                                                                            ##STR56##                                                                            (CH.sub.2).sub.3                                                                     ##STR57##        NMR (200 MHz in DMSO)                                                         ,7-2,2:m:18 H,                                                                2,4-4,6:m:17 H,                                                               6,4-7,8:m:12 H                                                                α.sub.D = +16                                                           (c = 1, MeOH)             18                                                                                  ##STR58##                                                                              --                                                                                  ##STR59##                                                                            (CH.sub.2).sub.2                                                                     ##STR60##        165                       19                                                                                  ##STR61##                                                                              --                                                                                  ##STR62##                                                                            (CH.sub.2).sub.2                                                                     ##STR63##        148                       20                                                                                  ##STR64##                                                                              CH.sub.2                                                                            ##STR65##                                                                            (CH.sub.2).sub.3                                                                     ##STR66##        240                       21                                                                                  ##STR67##                                                                              CH.sub.2                                                                            ##STR68##                                                                            (CH.sub.2).sub.3                                                                     ##STR69##        172                       22                                                                                  ##STR70##                                                                              CH.sub.2                                                                            ##STR71##                                                                            (CH.sub.2).sub.2                                                                     ##STR72##        149                       __________________________________________________________________________

EXAMPLE 23

Tablet comprising:

Compound 4 250 mg

Lactose 80 mg

Crosslinked polyvidone 20 mg

Methyl hydroxypropyl cellulose 10 mg

Hydrogenated castor oil 40 mg

EXAMPLE 24

Enteric tablet comprising:

Tablet:

Compound 4 250 mg

Hydroxypropyl cellulose 6 mg

Lactose 62 mg

Microcrystalline cellulose 60 mg

Carboxymethyl starch 12 mg

Polyethylene glycol 6000 10 mg

Coating:

Endraget L 100 1 mg

Dibutyl phthalate 1 mg

Isopropyl alcohol (evaporated) 28 mg

EXAMPLE 25

Solution to be taken orally, comprising:

Compound 4 100 mg

Ethyl alcohol 100 mg

Propylene glycol 50 mg

Polyvidone excipient 20 mg

Glycerol 50 mg

Artificial flavoring 2.5 mg

Purified water qsp 1.0 mg

EXAMPLE 26

Injectable suspension containing:

Compound 4 50 mg

Polysorbate 80 1.5 mg

Polyoxyethylene glycol 20 mg

Methyl and propyl parahydroxybenzoate 1.5 mg

Sorbitol 30 mg

Polyvidone excipient 10 mg

Water for injectable preparations qsp 1 mg

EXAMPLE 27

Gelatin capsule comprising:

Compound 4 from 2.5 to 250 mg

Modified maize starch 50 mg

Talc 25 mg

Anhydrous colloidal silica 1 mg

Stearic acid 10 mg

Lactose qsp 100 mg

EXAMPLE 28

Suppository comprising:

Compound 4 150 mg

Solid semisynthetic glycerides qsp

What is claimed is:
 1. A quaternary basic amide of the formula ##STR73##in which Ar is a phenyl which is mono- or di-substituted by a C₁ -C₄alkoxy, a halogen or a trifluoromethyl group;T is a direct bond, ahydroxymethylene group, an alkoxymethylene group in which the alkoxygroup is C₁ -C₄, or a C₁ -C₅ -alkylene group; Ar' is a phenyl which isunsubstituted or mono- or poly-substituted by a substituent selectedfrom the group consisting of a halogen atom, a trifluoromethyl, a C₁ -C₄-alkoxy and a C₁ -C₄ -alkyl, said substituents being identical ordifferent; a thienyl; a benzothienyl; a naphthyl; or an indolyl; R ishydrogen, a C₁ -C₄ -alkyl, an ω-(C₁ -C₄)alkoxy(C₂ -C₄)alkyl, or an ω-(C₂-C₄)alkanoyloxy(C₂ -C₄)alkyl; Q is hydrogen; or else Q and R togetherform a 1,2-ethylene, 1,3-propylene or 1,4-butylene group; Am.sup.⊕ isselected from the group consisting of a 1-azoniabicyclo 2.2.2!octane,4-phenyl-1-azoniabicyclo 2.2.2!octane and 4-benzyl-1-azoniabicyclo2.2.2!octane; and A.sup.⊖ is a pharmaceutically acceptable anion.
 2. Aquaternary basic amide of formula (I) according to claim 1, wherein T isa direct bond or a methylene group.
 3. A quaternary basic amide offormula (I) according to claim 1, wherein Q and R together form a1,2-ethylene 1,3-propylene or 1,4-butylene group.
 4. A quaternary basicamide according to claim 1 wherein Ar is selected from the groupconsisting of 3-isopropoxyphenyl, 3,5-difluoromethylphenyl and3-chlorophenyl.
 5. A quaternary basic amide according to claim 1 whereinAr' is selected from the group consisting of 3,4-dichlorophenyl and3,4-difluorophenyl.
 6. A quaternary basic amide according to claim 1wherein A.sup.⊖ is an anion selected from the group consisting ofchloride, bromide, iodide, hydrogensulfate, methanesulfonate,paratoluenesulfonate and acetate.
 7. A quaternary basic amide accordingto claim 1 wherein:Ar is a 3-isopropoxyphenyl; T is a methylene group;Ar' is a 3,4-difluorophenyl or a 3,4-dichlorophenyl; Q and R togetherform a 1,3-propylene group or a 1,4-butylene group; and Am.sup.⊕ is a4-phenyl-1-azoniabicyclo2.2.2!octane or a 4-benzyl-1-azoniabicyclo-2.2.2!octane.
 8. A quaternary basic amide according to claim 1wherein:Ar is a 3,5-ditrifluoromethylphenyl; T is a direct bond; Ar' isa 3,4-dichlorophenyl; Q and R together form a 1,2-ethylene group; andAm.sup.⊕ is a 4-phenyl-1-azoniabicyclo 2.2.2!octane or a4-benzyl-1-azoniabicyclo- 2.2.2!octane.
 9. A quaternary basic amideaccording to claim 1 wherein:Ar is a 3-chlorophenyl; T is a methylenegroup; Ar' is a 3,4-dichlorophenyl; Q and R together form a 1,2 ethylenegroup or a 1,3-propylene group; and Am.sup.⊕ is a4-phenyl-1-azoniabicyclo 2.2.2!octane or a 4-benzyl-1-azoniabicyclo-2.2.2!octane.
 10. A pharmaceutical composition comprising an effectiveamount of a compound as claimed in claim 1 and a pharmaceuticallyacceptable excipient.
 11. A pharmaceutical composition in the form of adosage, unit, containing an effective amount of a compound of formula(I) according to claim 1 as active principle, and at least onepharmaceutical excipient.
 12. A pharmaceutical composition comprising aneffective amount of a compound as claimed in claim 2 and apharmaceutically acceptable excipient.
 13. A pharmaceutical compositioncomprising an effective amount of a compound as claimed in claim 3 and apharmaceutically acceptable excipient.
 14. A pharmaceutical compositioncomprising an effective amount of a compound as claimed in claim 4 and apharmaceutically acceptable excipient.
 15. A pharmaceutical compositioncomprising an effective amount of a compound as claimed in claim 5 and apharmaceutically acceptable excipient.
 16. A pharmaceutical compositioncomprising an effective amount of a compound as claimed in claim 6 and apharmaceutically acceptable excipient.
 17. A pharmaceutical compositioncomprising an effective amount of a compound as claimed in claim 7 and apharmaceutically acceptable excipient.
 18. A pharmaceutical compositioncomprising an effective amount of a compound as claimed in claim 8 and apharmaceutically acceptable excipient.
 19. A pharmaceutical compositioncomprising an effective amount of a compound as claimed in claim 9 and apharmaceutically acceptable excipient.